Project Summary/Abstract Genomic Loci Modulating Biomechanics and Glaucoma in Recombinant Inbred Mice Glaucoma is a major cause of blindness and current treatments are insufficient. Here we propose novel studies to identify genomic loci associated with risk factors for glaucoma; specifically, we search for loci modulating the biomechanical properties of the sclera, thought to influence how intraocular pressure (IOP) insult is transmitted to optic nerve head (ONH) cells and tissues. Our central hypothesis is that specific genomic loci and associated molecular networks determine scleral biomechanical properties (stiffness and viscoelasticity) and are related to the risk of developing glaucomatous optic neuropathy. We propose 2 specific aims (SA?s) to test this hypothesis. Both aims use the BXD recombinant inbred (RI) mouse set, a well-characterized mouse genetic reference panel providing a powerful tool for quantitative trait locus (QTL) analysis. In SA1, we will measure the biomechanical properties of the sclera in BXD RI substrains and carry out QTL analysis to identify genomic loci that associate with scleral stiffness and viscoelasticity. In SA2, we will expose mice to the insult of elevated IOP (both steady and unsteady), and investigate whether extreme values of scleral stiffness and viscoelasticity predispose these animals to ONH astrocyte activation, thought to play an important early role in glaucomatous ONH changes. This project is innovative for several reasons. It represents a novel use of a powerful genetic reference panel (the BXD RI mouse set) to study and identify risk factors for glaucoma. In so doing, the proposed work is, to our knowledge, the first attempt to identify genes associated with scleral biomechanical properties in an unbiased screen, and to investigate whether such properties are associated with early markers of glaucomatous change. Further, this proposal uses novel technology, first developed to measure outflow facility in mouse eyes, to study how the sclera and ONH astrocytes respond to both steady and unsteady pressure insults. We expect, as suggested by our preliminary data, to discover genomic loci that associate with scleral biomechanical properties. Doing so is the first step towards identifying gene networks that determine scleral stiffness and viscoelasticity, two properties that indirectly influence the biomechanical insult that ONH cells experience in glaucoma. The benefits will be twofold. First, these discoveries would provide a powerful tool to better understand the role of scleral biomechanics in the pathophysiology of retinal ganglion cell loss in glaucoma. Second, they would motivate studies in humans, potentially identifying novel risk factors for development of glaucoma in clinical populations.